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Nucleoside analogues: mechanisms of drug resistance and reversal strategies

Leukemia volume 15, pages 875–890 (2001)Cite this article

Abstract

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.

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Acknowledgements

Carlos Galmarini is a recipient of the ‘Michel Clavel’ grant. The authors acknowledge the support of the Ligue Contre le Cancer du Rhône and the Alberta Cancer Foundation and National Cancer Institute of Canada.

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Authors and Affiliations

  1. Unité INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médécine Rockefeller, Lyon, France

    CM Galmarini & C Dumontet

  2. Department of Oncology, Medical and Experimental Oncology, University of Alberta, Edmonton, Alberta, Canada

    JR Mackey

  3. Service d'Hématologie, Centre Hospitalier Lyon Sud, France

    C Dumontet

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Galmarini, C., Mackey, J. & Dumontet, C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15, 875–890 (2001). https://doi.org/10.1038/sj.leu.2402114

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